NM_000033.4(ABCD1):c.1865+1G>A AND Adrenoleukodystrophy

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Dec 23, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000012067.13

Allele description [Variation Report for NM_000033.4(ABCD1):c.1865+1G>A]

NM_000033.4(ABCD1):c.1865+1G>A

Gene:

ABCD1:ATP binding cassette subfamily D member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq28

Genomic location:

Preferred name:

NM_000033.4(ABCD1):c.1865+1G>A

HGVS:

NC_000023.11:g.153743072G>A
NG_009022.2:g.23205G>A
NG_147801.1:g.442G>A
NM_000033.4:c.1865+1G>AMANE SELECT
LRG_1017t1:c.1865+1G>A
LRG_1017:g.23205G>A
NC_000023.10:g.153008526G>A
NM_000033.3:c.1865+1G>A

Nucleotide change:

IVS8DS, G-A, +1

Links:

OMIM: 300371.0024; dbSNP: rs1569541198

NCBI 1000 Genomes Browser:

rs1569541198

Molecular consequence:

NM_000033.4:c.1865+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Adrenoleukodystrophy (ALD)
Synonyms:: ADDISON DISEASE AND CEREBRAL SCLEROSIS; BRONZE SCHILDER DISEASE; MELANODERMIC LEUKODYSTROPHY; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0018544; MedGen: C0162309; OMIM: 300100

Recent activity

Clear Turn Off Turn On

mitochondrial basic amino acids transporter isoform X1 [Gymnodraco acuticeps]
mitochondrial basic amino acids transporter isoform X1 [Gymnodraco acuticeps]
gi|1839648834|ref|XP_034087635.1|

Protein
Exudative vitreoretinopathy, X-linked
Exudative vitreoretinopathy, X-linked

MedGen
C4016494[conceptid] (1)
MedGen

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000032301	OMIM	no assertion criteria provided	Pathogenic (Dec 1, 2001)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV004298791	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 23, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11810273, 16199547, 11748843, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000032301

OMIM

no assertion criteria provided

Pathogenic
(Dec 1, 2001)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV004298791

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 23, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Characterisation of two mutations in the ABCD1 gene leading to low levels of normal ALDP.

Guimarães CP, Lemos M, Menezes I, Coelho T, Sá-Miranda C, Azevedo JE.

Hum Genet. 2001 Dec;109(6):616-22. Epub 2001 Oct 26.

PubMed [citation]

PMID:: 11810273

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000032301.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

Guimaraes et al. (2001) found a splice site mutation in the ABCD1 gene which was associated with production of a small quantity of correctly spliced mRNA molecules and a small amount of ALD protein detected by Western blot analysis. The atypical and relatively mild early course of the patient was attributed to the existence of some normal ALDP. The patient was a 23-year-old man who had developed normally until the age of 9 years, when he was diagnosed with Addison disease. At that time, no neurologic involvement could be observed. Five years later, he was biochemically diagnosed with adrenoleukodystrophy (ALD; 300100); VLCFA levels were found to be increased in both plasma and skin fibroblasts. At the age of 21 years, muscular weakness and difficulty in walking led him to a new clinical evaluation; spastic paraparesis with neurophysiologic abnormalities with an altered spinal cord MRI and a normal cerebral MRI were found. Eighteen months later, the patient displayed a cerebral AMN subphenotype associated with an affected cerebellum. He was in a vegetative state at the time of report.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004298791.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 11810273). ClinVar contains an entry for this variant (Variation ID: 11315). Disruption of this splice site has been observed in individual(s) with clinical features of adrenoleukodystrophy (PMID: 11810273). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 8 of the ABCD1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ABCD1 are known to be pathogenic (PMID: 11748843).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine